Dasatinib (SPRYCEL®) 140 mg Once Daily (QD) vs 70 mg Twice Daily (BID) in Patients (pts) with Advanced Phase Chonic Myeloid Leukemia (ABP-CML) or Ph(+) ALL Who Are Resistant or Intolerant to Imatinib (im): Results of the CA180-035 Study.

Dasatinib (SPRYCEL^®, formerly BMS-354825), an oral multi-targeted kinase inhibitor of BCR-ABL and SRC kinases, has been shown to be safe and effective at 70 mg BID in pts with CML and Ph(+) ALL who are resistant or intolerant to im. Based on a previous phase I study, in which QD dosing was as effective as BID dosing, a dose-optimization study was performed. CA180035 is a randomized, global multicenter, open-label trial of dasatinib 140 mg QD versus 70 mg BID in pts with ABP-CML (accelerated or blastic phase) or Ph(+)ALL that were resistant to or intolerant of im. Patients were stratified by phase of disease (accelerated, myeloid blast, or lymphoid blast/Ph(+)ALL) and by prior im (resistant or intolerant). The primary objective of the study was to compare the major hematologic response (MaHR) rate between the 2 regimens. Dose escalation to 180 mg QD or 90 mg BID was allowed for inadequate response, and dose reduction to 100 or 80 mg QD or 50 or 40 mg BID for drug toxicity. Evaluations consisted of weekly blood counts for the first 12 wks, and bone marrow cytogenetics every 3 months (mo) in patients with complete hematologic response (CHR) and BCR-ABL mutation analysis at baseline and at end of study. From June 2005 through March 2006, 612 pts were randomized: 56% of the pts were male with median (med) age of 55 years and med time from CML diagnosis of 58 mo. All pts received prior im: 42% had >600 mg/day, and 37% were treated >3 years. Other prior therapy included interferon in 42% of pts, chemotherapy in 57% of pts and stem cell transplant in 14% of pts. With a minimum follow-up of 4 mo, 42% of pts have been discontinued, mostly due to disease progression. The MaHR rate was 35% including 21% CHR and the major cytogenetic response (MCyR) rate was 33%, including 23% complete cytogenetic response (CCyR). The most common non-hematologic drug-related toxicities included diarrhea (24%, gr 3–4: 3%), headache (17%, gr 3–4: 1%), nausea (17%, gr 3–4: 2%), pleural effusion (15%, gr 3–4: 4%), and fatigue (12%, gr 3–4: 3%). Hematologic toxicity included neutropenia gr 3 and gr 4 in 22% and 40% of pts, respectively, and thrombocytopenia gr 3 and gr 4 in 16% and 50% of pts, respectively. Dose reductions were required in 23% of pts and dose interruptions were required in 43% of pts, both due mostly to non-hematologic toxicity. This is the first direct comparison of the 70 mg BID vs 140 mg QD dasatinib schedules in pts with ABP-CML or Ph(+)ALL. Updated efficacy and safety data, including response by baseline mutation analysis, on all pts with a minimum of 6-months follow-up will be presented at the meeting.